Laser photothermal effect is a successful approach to tumor destruction since tumor tissue is more sensitive to temperature increases than normal tissue. In the past selective photothermal therapy using an in situ light-absorbing agent or nanoparticles has been developed. While photothermal interaction leads to acute, large-scale and controllable tumor destruction, its long-term effects are rather limited, particularly when treating metastatic cancers. However, laser-tissue thermal interaction can be used in combination with immunotherapy, as thermally destroyed tumor cells could serve as sources of tumor antigens, priming the host immune system. Laser immunotherapy (LIT) was developed as a synergistic approach to treat cancer systemically, through both local laser irradiation and immunological stimulation. LIT has shown great potential in treating late-stage, metastatic cancers, both in pre-clinical studies and in preliminary clinical trials. Interstitial laser immunotherapy (ILIT), using a fiber with a cylindrical active diffuse lens, can be an attractive alternative approach to overcome the challenges of non-invasive selective photothermal therapy, particularly when facing deep-seated tumors and highly pigmented skins.
The immunomodulatory effects of thermal interaction have been categorized in three different temperature ranges: fever range (39-40° C.), heat shock range (41-43° C.) and cytotoxic range (>43° C.) [14]. In the first two ranges, the thermal effect modifies both tumor cells and immune cells to stimulate host tumor-specific immune response. In the third range, high temperatures can lead to direct destruction of tumor cells, releasing a large load of tumor antigens; these are taken up by antigen-presenting cells, particularly dendritic cells, and delivered to lymph nodes where they induce an antitumor immune response. The optimal outcome of photothermal tissue interaction, therefore, is to destroy as many target tumor cells as possible, while preserving tumor proteins to be recognized by the host immune system. Laser immunotherapy can achieve a maximum temperature of up to 60 to 70° C., well within the cytotoxic range. At these temperatures, cell death occurs through coagulation necrosis. The aim of laser immunotherapy is to control the target tissue temperature at an optimal level, which will be determined under different conditions, for the treatment of tumors.
Since temperature plays an important role in laser phototherapy, accurate temperature measurement and control are crucial. Current non-invasive methods in tissue temperature measurement include infrared thermography, ultrasound imaging, and magnetic resonance thermometry (MRT). Infrared thermography can provide sensitive, real-time detection; however, this can measure surface temperature only. Ultrasound can reach deep tissues, but it has relatively low sensitivity and accuracy. Temperature measurements, based on water proton resonance frequency (PRF) in MRT, exploit the temperature dependency of the water proton's chemical shift to determine tissue temperature of each voxel; and this has been used for interstitial laser therapy. MRT provides non-invasive three-dimensional temperature distribution with high sensitivity. However, MRT has relatively low temporal resolution, and its cost and complexity severely limit its practical applications.
Previous reports have shown that photoacoustic (PA) imaging can be used for temperature measurements in tissue. PA signal amplitude shows a linear correlation with temperatures in the range of 10 to 55° C., just below the desired threshold temperature of biological responses. It is therefore an objective of the present invention to use PA imaging in a method and apparatus to provide tissue temperature monitoring and laser phototherapy control to optimize thermal effects and for modulating immune responses. It is a further objective of the present invention to provide an interstitial PA sensor for the real-time measurement of tissue temperature, as well as other tissue properties, during interstitial laser phototherapy.